EP1323710B1 - Composes azotes a noyau a cinq elements - Google Patents

Composes azotes a noyau a cinq elements Download PDF

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Publication number
EP1323710B1
EP1323710B1 EP01974716A EP01974716A EP1323710B1 EP 1323710 B1 EP1323710 B1 EP 1323710B1 EP 01974716 A EP01974716 A EP 01974716A EP 01974716 A EP01974716 A EP 01974716A EP 1323710 B1 EP1323710 B1 EP 1323710B1
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group
apci
compound
mixture
compound according
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EP1323710A4 (fr
EP1323710A1 (fr
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Kosuke Yasuda
Hiroshi Morimoto
Saburo Kawanami
Masataka Hikota
Takeshi Matsumoto
Kenji Arakawa
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Mitsubishi Tanabe Pharma Corp
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Mitsubishi Tanabe Pharma Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel nitrogen-containing 5-membered ring compound having superior dipeptidylpeptidase IV (DPPIV) inhibitory action that is useful as a pharmaceutical.
  • DPPIV dipeptidylpeptidase IV
  • Dipeptidylpeptidase IV is a kind of serine protease that specifically hydrolyzes a dipeptide of Xaa-Pro or Xaa-Ala (where Xaa may be any amino acid) from the N terminus of a polypeptide chain.
  • DPPIV also called to as CD26
  • CD26 DPPIV
  • researchers There are various reports regarding the role of DPPIV (also called to as CD26) in the body and its relationship with diseases ( Holst, et al., Diabetes, Vol. 47, pp. 1663-1670, 1998 ; Augustyns, et al., Current Medicinal Chemistry, Vol. 6, pp. 311-327, 1999 ; Meester, et al., Immunol. Today, Vol. 20, pp. 367-375, 1999 ; and, Fleicher, et al., Immunol. Today, Vol. 15, pp. 180-184, 1994 ).
  • GLP-1 (glucagon-like peptide 1) is a peptide hormone that mainly acts in the pancreas after being secreted from the lower small intestine after meals, and primarily has the function of amplifying glucose-induced insulin secretion. In addition, there are several reports suggesting that GLP-1 has an appetite-suppressing action. DPPIV hydrolyzes GLP-1, forming an inactive or antagonistic peptide.
  • Substances that inhibit the enzyme activity of DPPIV enhance the insulin secretion response to oral glucose loading by enhancing the action of intrinsic GLP-1, thereby improving impaired glucose tolerance.
  • DPPIV inhibitors are considered to be useful for the prophylaxis and treatment of diabetes (particularly type 2 diabetes), etc. Also, they are expected to be effective for the prophylaxis and treatment of other diseases induced or exacerbated by impaired glucose tolerance (including hyperglycemia (such as postprandial hyperglycemia), hyperinsulinemia, diabetes complications (such as renal disorder and neurological disorder), lipid metabolism disorder and obesity, etc.).
  • hyperglycemia such as postprandial hyperglycemia
  • hyperinsulinemia such as postprandial hyperglycemia
  • diabetes complications such as renal disorder and neurological disorder
  • lipid metabolism disorder and obesity lipid metabolism disorder and obesity, etc.
  • DPPIV inhibitors are also expected to be effective for the prophylaxis and treatment of diseases that are to be improved by enhancing the appetite-suppressing action of GLP-1 (including overeating and obesity, etc.).
  • DPPIV (CD26) present on the surface of T cells is strongly upregulated following T cell activation, and plays an important role in the activation and proliferation of T cells.
  • T cell activity is known to be suppressed when DPPIV (CD26) is blocked by antibodies or inhibitory substances.
  • DPPIV (CD26) positive rate of peripheral blood T cells is elevated in rheumatoid patients, and high levels of DPPIV activity have been detected in the urine of nephritis patients.
  • DPPIV (CD26) is also thought to play an important role in the entry of HIV into lymphocytes.
  • substances that inhibit DPPIV are expected to demonstrate prophylactic and therapeutic effects against diseases including autoimmune diseases (such as arthritis and rheumatoid arthritis), osteoporosis, acquired immunodeficiency syndrome (AIDS) and rejections of transplanted organs and tissues.
  • diseases including autoimmune diseases (such as arthritis and rheumatoid arthritis), osteoporosis, acquired immunodeficiency syndrome (AIDS) and rejections of transplanted organs and tissues.
  • the present invention provides a novel aliphatic nitrogen-containing 5-membered ring compound having an excellent DPPIV inhibitory action.
  • the present invention relates to an aliphatic nitrogen-containing 5-membered ring compound represented by the formula [I]: wherein symbols in the formula have the following meanings;
  • optical isomers based on an asymmetric carbon can be present in the objective compound [I] of the present invention, the present invention includes any of these optical isomers as well as mixtures thereof.
  • isomers (cis form or trans form) are also present based on the relative positions of substituents with respect to the standard plane of a cyclic group, the present invention also includes any of these isomers as well as mixtures thereof.
  • a lower alkyl group, a lower alkylthio group, a lower alkylsulfonyl group, a lower alkoxy group and a lower alkylamino group includes linear or branched groups having 1 to 6 carbon atoms, and particularly those having 1 to 4 carbon atoms.
  • a lower alkanoyl group and a lower alkanoylamino group include linear or branched groups having 2 to 7 carbon atoms, and particularly those having 2 to 5 carbon atoms.
  • a lower cycloalkyl group and lower cycloalkenyl group include those having 3 to 8 carbon atoms, and particularly 3 to 6 carbon atoms.
  • a lower alkylene group includes linear or branched groups having 1 to 6 carbon atoms, and particularly 1 to 4 carbon atoms.
  • a lower alkenyl group and lower alkenylene group include those having 2 to 7 carbon atoms, and particularly 2 to 5 carbon atoms.
  • examples of a halogen atom include fluorine, chlorine, bromine and iodine.
  • hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or lower alkoxy lower alkyl group represented by R 1
  • R 1 specific examples of "hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or lower alkoxy lower alkyl group” represented by R 1 include hydrogen atom, methyl group, hydroxymethyl group, methoxymethyl group, etc.
  • hydrogen atom or a lower alkyl group (such as methyl group, etc.) is preferred.
  • cyclic group R 2 may include: "a piperidyl group (1-piperidyl group, etc.), a piperazinyl group (1-piperazinyl group, etc.), a morpholinyl group (4-morpholinyl group, etc.), an indolinyl group (1-indolinyl group, etc.), an isoindolinyl group (2-isoindolinyl group, etc.), a thiazolopyridyl group (thiazolo[5,4-b]pyridin-2-yl group, etc.), etc.”
  • particularly preferred examples may include:
  • the substituent(s) of the cyclic group R 2 is/are selected from the following "substituents of Group A". Among them, “substituents of Group A'" are more preferred. ------Substituents of Group A: -----
  • the nitrogen-containing monocyclic 6-membered aromatic heterocyclic group specific examples may include "a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a pyranyl group, etc.” ---Substituents of Group A' (particularly preferred substituents of Group A):-----
  • R 2 include a monocyclic or bicyclic nitrogen-containing heterocyclic group which may be substituted.
  • a trans-isomeric compound is more preferred from the viewpoint of obtaining a higher DPPIV inhibitory activity. That is, among the objective compound [I] of the present invention wherein B is CH, a compound having the following partial structure: or a pharmaceutically acceptable salt thereof is preferred.
  • R 2 is a cyclic group which may have 1 to 3 substituents which are the same or different, selected from the substituents of Group A', where the cyclic portion is a group selected from a piperidyl group, a piperazinyl group, a morpholinyl group, an indolinyl group, an isoindolinyl group, and a thiazolopyridyl group may be exemplified (Compound Group 4).
  • compounds group wherein B is CH, X is a single bond, and A is -CH 2 -; compounds group wherein B is CH, X is a single bond, A is -CH 2 -, and R 1 is hydrogen atom or a lower alkyl group; compounds group wherein B is CH, X is a single bond, and A is -S-; compounds group wherein B is CH, X is a single bond, A is -S-, and R 1 is hydrogen atom or a lower alkyl group; and the like may be exemplified.
  • the objective compound [I] or a pharmaceutically acceptable salt thereof of the present invention has superior inhibitory action on the enzyme activity of DPPIV. They have superior inhibitory action especially on human DPPIV. In addition, they also exhibit high selectivity with respect to DPPIV (namely, type IV dipeptidylpeptidase) in various serine proteases (e.g., plasmin, thrombin, prolylendopeptidase, trypsin and dipeptidylpeptidase II).
  • DPPIV namely, type IV dipeptidylpeptidase
  • serine proteases e.g., plasmin, thrombin, prolylendopeptidase, trypsin and dipeptidylpeptidase II.
  • the objective compound [I] or a pharmaceutically acceptable salt thereof of the present invention improves insulin secretion response to oral glucose loading by means of its DPPIV inhibitory action.
  • the objective compound [I] or a pharmaceutically acceptable salt thereof of the present invention is useful as prophylactic or therapeutic agents for diseases relating to DPPIV (diseases mediated by DPPIV), that is, diseases which is expected to be alleviated by inhibiting DPPIV enzyme activity.
  • diabetes e.g., type 1 diabetes and type 2 diabetes
  • hyperglycemia such as postprandial hyperglycemia
  • hyperinsulinemia such as postprandial hyperglycemia
  • diabetes complications such as renal disorder and neurological disorder
  • obesity overeating
  • lipid metabolism disorder such as hyperlipemia including hypertriglyceridemia and others
  • autoimmune diseases such as arthritis and rheumatoid arthritis
  • osteoporosis acquired immunodeficiency syndrome (AIDS) and rejection of transplanted organs and tissues.
  • AIDS acquired immunodeficiency syndrome
  • the objective compound [I] or a pharmaceutically acceptable salt thereof of the present invention is particularly useful as a prophylactic or therapeutic agent of diabetes (and particularly type 2 diabetes).
  • the compound of the present invention has low toxicity, and thus, has a high level of safety when used as a pharmaceutical compound. Furthermore, it also demonstrates superior pharmacokinetic characteristics [including bioavailability, in vitro metabolic stability (stability in human liver homogenates), P450 inhibitory action and protein binding capabilities, etc.].
  • the DPPIV inhibitory action of the compound of the present invention as well as its pharmaceutical efficacy (including anti-hyperglycemia effect and the effect of improving insulin secretion response to glucose loading) based on that action can be confirmed by known methods or methods equivalent to those methods ( WO 98/19998 ; WO 00/34241 ; Holst, et al., Diabetes, Vol. 47, pp. 1663-1670, 1998 ; Augustyns, et al., Current Medicinal Chemistry, Vol. 6, pp. 311-327, 1999 ; Meester, et al., Immunol. Today, Vol. 20, pp. 367-375, 1999 ; and, Fleicher, et al., Immunol. Today, Vol. 15, pp. 180-184, 1994 ).
  • the objective compound [I] of the present invention can be used for a pharmaceutical use either in a free form or in a form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt of the compound [I] include an inorganic acid salt such as hydrochloride, sulfate, phosphate or hydrobromide, and an organic acid salt such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate or maleate, etc.
  • a salt with a base for example, an alkali metal salt such as a sodium salt, a potassium salt, etc., or an alkaline earth metal salt such as a calcium salt and the like
  • a base for example, an alkali metal salt such as a sodium salt, a potassium salt, etc., or an alkaline earth metal salt such as a calcium salt and the like
  • the objective compound [I] or the pharmaceutically acceptable salt thereof of the present invention include its internal salts, adducts, solvates and hydrates.
  • the objective compound [I] or pharmaceutically acceptable salts thereof of the present invention can be administered orally or parenterally and used as commonly used pharmaceutical preparations, such as tablets, granules, capsules, powders, injection solution and inhalants.
  • the compound of the present invention for example, can be used with pharmaceutically acceptable general excipients such as binder, disintegrator, extenders, fillers and lubricants, or diluents, and prepared according to the usual method.
  • the administration dose of the objective compound [I] or pharmaceutically acceptable salts thereof of the present invention may vary depending on the administration method, age, weight and condition of a patient, and it is generally about 0.01 to 300 mg/kg, preferably about 0.1 to 30 mg/kg per day.
  • the objective compound [I] of the present invention can be prepared according to the following (Process A) to (Process D), but it is not limited to these processes.
  • the objective compound [I] of the present invention can be prepared by reacting a compound represented by the formula [II]: wherein Z 1 represents a reactive residue and A has the same meaning as defined above, with a compound represented by the formula [III]: wherein R 1 , R 2 , B and X have the same meanings as defined above, or salts thereof, and optionally, by making the products into a pharmaceutically acceptable salt.
  • a salt with an inorganic acid such as hydrochloride and sulfate, or a salt with an inorganic base such as an alkali metal salt and an alkaline earth metal salt can be used.
  • reactive residue of Z 1 commonly used reactive residues such as a halogen atom, a lower alkylsulfonyloxy group and an arylsulfonyloxy group can be used, among which the halogen atom is particularly preferred.
  • reaction of the compound [II] with the compound [III] or the salt thereof can be carried out in a suitable solvent or without solvent in the presence or absence of an acid acceptor.
  • any solvents may be suitable as long as it does not adversely affect to the reaction, and, for example, acetonitrile, methanol, ethanol, isopropyl alcohol, propyl alcohol, acetone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ether, dioxane, ethyl acetate, toluene, methylene chloride, dichloroethane, chloroform or a mixed solvent of these solvents can be suitably used.
  • This reaction suitably proceeds at 0 to 120°C, particularly at room temperature to 80°C.
  • an inorganic base for example, alkali metal hydride such as sodium hydride, alkali metal carbonate such as sodium carbonate and potassium carbonate, alkali metal alkoxide such as sodium methoxide, alkali metal such as sodium, and alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, etc.
  • an organic base for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, etc.
  • the compound represented by the formula [I-a]: wherein R 21 represents a monocyclic or bicyclic nitrogen-containing heterocyclic group which may be substituted, and R 1 , A and B have the same meanings as defined above, can be prepared by reacting a compound represented by the formula [IV]: wherein R represents a protective group for the amino group, and R 1 , A and B have the same meanings as defined above, or a salt thereof with a phosgene or an equivalent thereof, and subsequently, further reacting with a compound represented by the formula [V]: R 21 H [V] wherein R 21 has the same meaning as defined above, to obtain a compound represented by the formula [VI]: wherein R; R 1 , R 21 , A and B have the same meanings as defined above, or a salt thereof, and further removing the protective group (R) for the amino group from the product.
  • reaction with the compound [V] can be carried out in a suitable solvent or without solvent in the presence of a phosgene or an equivalent thereof and an acid acceptor.
  • the phosgene or the equivalent thereof triphosgene, diphosgene, carbonyldiimidazol, 4-nitrophenyl-chloroformate, etc. can be suitably used.
  • an inorganic base for example, alkali metal hydride such as sodium hydride, alkali metal carbonate such as sodium carbonate and potassium carbonate, alkali metal amide such as sodium amide and lithium amide, alkali metal alkoxide such as sodium methoxide, alkali metal such as sodium, and alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, etc.
  • an organic base for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, etc.
  • any solvents may be suitable as long as it does not adversely affect to the reaction, and, for example, methylene chloride, dichloroethane, chloroform, ether, tetrahydrofuran, ethyl acetate, toluene or a mixed solvent thereof can be suitably used.
  • the present reaction suitably proceeds at -78°C to 110°C, especially at 0°C to room temperature.
  • the following removal of the protective group (R) for an amino group of the compound [VI] can be carried out according to the conventional method, and it can be carried out, for example, in a suitable solvent or without solvent by an acid treatment, base treatment or catalytic reduction.
  • an inorganic acid such as hydrochloric acid, sulfuric acid, etc.
  • an organic acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.
  • an inorganic base for example, alkali metal hydride such as sodium hydride, etc., alkali metal carbonate such as sodium carbonate, potassium carbonate, etc., alkali metal amide such as sodium amide, lithium amide, etc., alkali metal alkoxide such as sodium methoxide, etc., alkali metal such as sodium, etc., and alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc.
  • an organic base for example, triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, pyridine, piperidine, dimethylaniline, dimethylaminopyridine, etc.
  • the catalytic reduction can be carried out by suitably using palladium-carbon, palladium hydroxide-carbon, platinum oxide or Raney nickel under hydrogen atmosphere.
  • any solvents may be suitable as long as it does not adversely affect to the reaction, and, for example, methanol, ethanol, isopropyl alcohol, propyl alcohol, dioxane, methylene chloride, chloroform, dichloroethane, ether, tetrahydrofuran, ethyl acetate, toluene or a mixed solvent thereof can be suitably used.
  • This reaction suitably proceeds at -78°C to 80°C, particularly at 0°C to room temperature.
  • a compound wherein B is CH and X is -CON(R 3 )CH 2 - or -Alk-CON(R 3 )CH 2 -, represented by the formula [I-d]: wherein X 3 represents -CON(R 3 )CH 2 - or -Alk-CON(R 3 )CH 2 -, and R 1 , R 2 , R 3 and A have the same meanings as defined above, can be prepared by reacting a compound represented by the formula [XIII] : wherein n is 0, 1, 2 or 3, P represents a resin residue, and R 1 , R 3 , A have the same meanings as defined above, with a compound represented by the formula [XII] R 2 -V 2 wherein V 2 represents -COOH or -Alk-COOH, or a salt thereof, and subsequently removing the linker and the resin residue portion represented by the formula [IX] from the reaction product.
  • Process D the reaction between the compound [XIII] and the compound [XII] or a salt thereof
  • a condensing agent and/or an acid acceptor in a suitable solvent or without solvent.
  • the linker and the resin residue portion are removed according to the conventional method, and if necessary, purification is carried out by, for example, extraction, distribution, reprecipitation, crystallization, recrystallization, various kinds of chromatographies, high performance chromatography, etc.
  • linker a group in which a resin residue (P) portion is removed from the group represented by the formula [IX] can be exemplified.
  • a resin that is used in a conventional solid phase synthesis can be used, and there may be mentioned, for example, a Merrifield resin (4-chloromethyl polystyrene resin, etc.), a Wang resin (4-benzyloxybenzyl alcohol resin, etc.), a hydroxymethyl polystyrene resin (4-hydroxymethyl polystyrene resin, etc.), etc.
  • any resin may be used as long as it does not adversely affect to the reaction, and it is suitably selected depending on the kind of the objective compound.
  • those with a particle diameter of 70 to 200 pm are preferably used, and a loading capacity is preferably 0.1 to 2 mmol/g.
  • O-benzotriazol-1-yl-N,N,N',N'-tetramethyluroniumhexafluorophosphate DCC (dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), chloroformates (for example, ethyl chloroformate and isobutyl chloroformate) and carbonyldiimidazole, etc.
  • DCC dicyclohexylcarbodiimide
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • chloroformates for example, ethyl chloroformate and isobutyl chloroformate
  • carbonyldiimidazole etc.
  • an additive such as a base (sodium carbonate, sodium hydrogencarbonate, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), 1-hydroxybenzotriazole, 1-hydroxysuccinimide, etc. can be added to the above condensing agent.
  • a base sodium carbonate, sodium hydrogencarbonate, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.
  • 1-hydroxybenzotriazole 1-hydroxysuccinimide, etc.
  • alkali metal hydroxide such as sodium hydroxide and potassium hydroxide
  • alkali metal hydrogencarbonate such as sodium hydrogencarbonate and potassium hydrogencarbonate
  • alkali metal carbonate such as sodium carbonate and potassium carbonate
  • an organic base triethylamine, pyridine, etc.
  • the following removal of the linker and the resin residue portion can be suitably carried out in a suitable solvent or without solvent by treating the product with trifluoroacetic acid, trifluoromethanesulfonic acid, hydrogen fluoride, hydrogen bromide, hydrogen chloride, etc, and a mixture thereof.
  • any solvents may be suitable as long as it does not adversely affect to the reaction, and, for example, methylene chloride, N-methyl morpholine, dimethylformamide, tetrahydrofuran, dimethylacetamide or a mixed solvent thereof can be suitably used.
  • the reaction in Process D suitably proceeds at 0 to 50°C, particularly at 0 to 30°C.
  • any solvents may be suitable as long as it does not adversely affect to the reaction, and, for example, methylene chloride, acetic acid, trifluoroacetic acid or a mixed solvent thereof can be suitably used.
  • the reaction suitably proceeds at 0 to 50°C, particularly at 0 to 30°C.
  • the starting material [II] of the present invention can be prepared, for example, according to the process described in International Patent Publications Nos. WO98/19998 , WO00/34241 and Reference Examples mentioned below (Reference Example 1 or 2), etc.
  • the compound [II] can be obtained by reacting a compound represented by the formula [20]: wherein A has the same meaning as defined above, with a compound represented by the formula [21]: Z 2 -CH 2 CO-Z 3 [21] wherein Z 2 and Z 3 represent a reactive residue which may be the same or different, in the presence of an acid acceptor (for example, triethylamine, etc.) to obtain a compound represented by the formula [22] : wherein Z 2 and A have the same meanings as defined above, and treating the product with a dehydrating agent (for example, phosphorous oxychloride, trifluoroacetic anhydride, etc.) according to the conventional method.
  • a dehydrating agent for example, phosphorous oxychloride, trifluoroacetic anhydride, etc.
  • the starting material [III] can be prepared, for example, by the same process as described in Reference Examples mentioned below (Reference Examples 7 to 10).
  • the compound [III] wherein X is -O-CH 2 - or -NHCH 2 - can be prepared by reacting a compound represented by the formula [23]: wherein V 3 represents a hydroxy group or an amino group, and R 1 and B have the same meanings as defined above, an amino group-protected material thereof or a salt thereof with a compound represented by the formula [24]: R 2 -Z 4 [24] wherein Z 4 represents a reactive residue and the other symbol has the same meaning as defined above, in the presence or absence of an acid acceptor (for example, an organic base such as triethylamine, diisopropylethylamine, etc., and an inorganic base such as sodium hydride, potassium carbonate, etc.), and, if necessary, removing the protective group for the amino group according to the conventional method.
  • an acid acceptor for example, an organic base such as triethylamine, diisopropylethylamine, etc., and an inorganic base such as sodium
  • any of the same protective groups commonly used as mentioned above R can be suitably used.
  • the compound [III] wherein X is -Alk-O- or -S- can be prepared by reacting a compound represented by the formula [25]: wherein V 4 represents a hydroxy group or a mercapto group and R 1 and B have the same meanings as defined above, an amino group-protected material thereof or a salt thereof with a compound represented by the formula [26a] or the formula [26b]: R 2 -Z 51 [26a] or R 2 -Alk-Z 52 [26b] wherein Z 51 and Z 52 represent a reactive residue and R 2 and Alk have the same meanings as defined above, in the presence or absence of an acid acceptor (for example, an organic base such as triethylamine, diisopropylethylamine, etc., and an inorganic base such as sodium hydride, potassium carbonate, etc.), and, if necessary, removing the protective group for the amino group according to the conventional method.
  • an acid acceptor for example, an organic base such as tri
  • the compound [III] wherein X is -COCH 2 N(R 3 )- or -SO 2 N(R 3 )- can be obtained by reacting a compound represented by the formula [27]: wherein V 5 represents -N(R 3 )H, and R 1 , R 3 and B have the same meanings as defined above, an amino group-protected material thereof or a salt thereof with a compound represented by the formula [28a] or the formula [28b]: R 2 -COCH 2 -Z 61 [28a] or R 2 -SO 2 -Z 62 [28b] wherein Z 61 and Z 62 represent a reactive residue and R 2 has the same meaning as defined above, in the presence or absence of an acid acceptor (for example, an organic base such as triethylamine, diisopropylethylamine, etc., and an inorganic base such as sodium hydride, potassium carbonate, etc.), and, if necessary, removing the protective group for the amino group according to the
  • the compound [III] wherein X is -CON(R 3 )-, -Alk-CON(R 3 )- or -SO 2 N(R 3 )- can be prepared by reacting the compound represented by the formula [27], an amino group-protected material thereof or a salt thereof, with a compound represented by the formula [29]: R 2 -V 6 [29] wherein V 6 represents -COOH, -Alk-COOH or -SO 3 H and R 2 has the same meaning as defined above, or a salt thereof in the presence of a condensing agent (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, etc.), and, if necessary, removing the protective group for the amino group according to the conventional method.
  • a condensing agent (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, etc.
  • the compound [III] wherein X is -CON(R 3 )CH 2 - or -Alk-CON(R 3 )CH 2 - can be prepared by reacting a compound represented by the formula [30]: wherein V 7 represents -N(R 3 )H, and R 1 , R 3 and B have the same meanings as defined above, an amino group-protected material thereof or a salt thereof, with a compound represented by the formula [31]: R 2 -V 8 [31] wherein V 8 represents -COOH or -Alk-COOH and R 2 has the same meaning as defined above, or a salt thereof in the presence of a condensing agent (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, etc.), and, if necessary, removing the protective group for the amino group according to the conventional method.
  • a condensing agent (1-ethyl-3-(3-dimethylaminopropyl)carbodi
  • the compound [III] wherein B isCH, X is -Alk-CO- and R 2 is a monocyclic or bicyclic nitrogen-containing heterocyclic group which may be substituted can be prepared by reacting a compound represented by the formula [32] : wherein V 9 represents -COOH and R 1 has the same meaning as defined above, an amino group-protected material thereof or a salt thereof, with a compound represented by the formula [33a]: R 22 -Alk-H [33a] wherein R 22 represents a monocyclic or bicyclic nitrogen-containing heterocyclic group which may be substituted and Alk has the same meaning as defined above, or a salt thereof, in the presence of a condensing agent (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, etc.), and, if necessary, removing the protective group for the amino group according to the conventional method.
  • a condensing agent (1-ethyl-3-(3-dimethyl
  • the compound [III] wherein B is CH, X is a single bond and R 2 is a monocyclic or bicyclic nitrogen-containing heterocyclic group which may be substituted can be prepared by reacting the compound represented by the formula [34]: wherein R 1 has the same meaning as defined above, an amino group-protected material thereof or a salt thereof, with a compound represented by the formula [33b]: R 22 -H [33b] wherein R 22 has the same meaning as defined above, in the presence of a reducing agent (sodium triacetoxyborohydride, etc.), and, if necessary, removing the protective group for the amino group according to the conventional method.
  • a reducing agent sodium triacetoxyborohydride, etc.
  • the compound [III] wherein B is CH, X is a single bond and R 2 is a group represented by the formula: can be prepared by reacting a compound represented by the formula [35]: wherein R 1 has the same meaning as defined above, an amino group-protected material thereof or a salt thereof, with a compound represented by the formula [36]: wherein Ar represents an arylene (phenylene, etc.) which may have a substituent(s), in the presence or absence of an acid acceptor (for example, an organic base such as triethylamine, diisopropylethylamine, etc., and an inorganic base such as sodium hydride, potassium carbonate, etc.), and, if necessary, removing the protective group for the amino group according to the conventional method.
  • an acid acceptor for example, an organic base such as triethylamine, diisopropylethylamine, etc., and an inorganic base such as sodium hydride, potassium carbonate, etc.
  • the compound [III] wherein B is CH, X is a single bonding arm and R 2 is a nitrogen-containing heterocyclic group represented by the formula: can be prepared by reacting the compound represented by the above-mentioned formula [35], an amino group-protected material thereof or a salt thereof, with a compound represented by the formula [37]: wherein Z 81 and Z 82 both represent a reactive residue, or a salt thereof, in the presence or absence of an acid acceptor (for example, an organic base such as triethylamine, diisopropylethylamine, etc., and an inorganic base such as sodium hydride, potassium carbonate, etc.), and, if necessary, removing the protective group for the amino group according to the conventional method.
  • an acid acceptor for example, an organic base such as triethylamine, diisopropylethylamine, etc., and an inorganic base such as sodium hydride, potassium carbonate, etc.
  • the protective group for the amino group any of
  • the compound [III] wherein X is -COO- can be prepared by reacting an amino group-protected material or,a salt of a compound represented by the formula [39]: wherein R 1 and B have the same meanings as defined above; with a compound represented by the formula [40]: R 2 -COCl [40] wherein R 2 has the same meaning as defined above, in the presence of an acid acceptor (dimethylaminopyridine, etc.), and, if necessary, removing the protective group for the amino group according to the conventional method.
  • an acid acceptor dimethylaminopyridine, etc.
  • the protective group for the amino group any of the same protective groups commonly used as mentioned above R can be suitably used.
  • the starting materials [20] to [40] can be prepared according to the known methods or in the same manner as mentioned in Reference Examples below.
  • the starting material [III] wherein B is CH cis/trans isomers are present, taking a cyclohexane ring as a standard plane.
  • R, R 1 , Z 1 , A and B have the same meanings as defined above.
  • a compound represented by the formula [IV] or a salt thereof can be prepared by reacting the compound represented by the above formula [II] with a compound represented by the formula [41] or a salt thereof to obtain a compound represented by the formula [42] or a salt thereof, and further reacting the same with a compound represented by the formula [43] or the formula [44].
  • Reaction between the compound [II] and the compound [41] or a salt thereof can be carried out in the presence or absence of an acid acceptor, in a suitable solvent or without solvent.
  • a suitable solvent any solvents may be suitable as long as it is not adversely affected to the reaction, and, for example, acetonitrile, methanol, ethanol, isopropyl alcohol, propyl alcohol, acetone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ether, dioxane, ethyl acetate, toluene, methylene chloride, dichloroethane, chloroform or a mixed solvent thereof can be suitably used.
  • This reaction suitably proceeds at 0 to 120°C, particularly at room temperature to 80°C.
  • an inorganic base for example, alkali metal hydride such as sodium hydride, alkali metal carbonate such as sodium carbonate and potassium carbonate, alkali metal alkoxide such as sodium methoxide, alkali metal such as sodium, and alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, etc.
  • an organic base for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, etc.
  • Reaction between the compound [42] or a salt thereof and the compound [43] or [44] can be carried out in the presence of an acid acceptor, in a suitable solvent or without solvent.
  • any solvents may be suitable as long as it is not adversely affected to the reaction, and, for example, acetonitrile, methanol, ethanol, isopropyl alcohol, propyl alcohol, acetone, tetrahydrofuran, ether, dioxane, ethyl acetate, toluene, methylene chloride, dichloroethane, chloroform, water or a mixed solvent thereof can be suitably used.
  • This reaction suitably proceeds at 0 to 120°C, particularly at room temperature to 80°C.
  • an inorganic base for example, alkali metal hydride such as sodium hydride, alkali metal carbonate such as sodium carbonate and potassium carbonate, alkali metal alkoxide such as sodium methoxide, alkali metal such as sodium, and alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, etc.
  • an organic base for example, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimethylaniline, dimethylaminopyridine, etc.
  • the compound [XIII] can be obtained by reacting a compound represented by the formula [52]: wherein V 12 represents protective groups for the amino group, and R 1 and R 3 have the same meanings as defined above, with a compound represented by the formula [53]: wherein P and n have the same meanings as defined above, according to a conventional method, in the presence of a reducing agent (for example, sodium triacetoxyborohydride, etc.), subsequently reacting the product in the presence of the compound [II] and an acid acceptor (diisopropylethylamine, etc.), and then, removing the protective group for the amino group according to the conventional method.
  • a reducing agent for example, sodium triacetoxyborohydride, etc.
  • an acid acceptor diisopropylethylamine, etc.
  • the protective group for the amino group any of the same protective groups commonly used as mentioned above R can be suitably used.
  • the compound [I] of the present invention or its starting material prepared according to the above is isolated in a free form or as a salt thereof, and purified. Salts can be prepared by subjecting to the salt-forming treatment conventionally used.
  • Isolation and purification can be carried out by applying the usual chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, various kinds of chromatographies and the like.
  • optical isomers such as racemic modifications, optically active substances, diastereomers, etc. can be present alone or as mixtures thereof.
  • a stereochemically pure isomer can be derived by using a stereochemically pure starting material or by separating an optical isomer according to the general separation process for racemic resolution. Also, diastereomeric mixtures can be separated according to the conventional method, for example, fractional crystallization or by chromatography.
  • Example 1 The compounds of Table 1 shown below (Examples 1-2 to 1-90, 1-92 to 1-109) were obtained in the same manner as in the above-mentioned Example 1-1 by using (S)-1-bromoacetyl-2-cyanopyrrolidine and corresponding starting materials.
  • Example 1-93 (Provided that the compound of Example 1-93 was obtained as a by-product of Example 1-33.)
  • Examples 5-1 to 5-12 in Table 5 were obtained in the same manner as in Examples 4-1 to 4-10 by using a resin compound obtained in Reference Example 4 in place of the resin compound of Reference Example 3 (2).
  • the compounds of Examples 5-13 to 5-30 in Table 5 were obtained in the same manner as in Example 4-11, using a resin compound obtained in Reference Example 4 in place of the resin compound of Reference Example 3 (2). Also, the compounds of Examples 5-31 to 5-36 in Table 5 were obtained in the same manner by using a resin compound obtained in Reference Example 5 (5).
  • a mixture comprising 500 mg of the resin compound obtained in the Reference Example 5 (5) and 0.5M methanesulfonic acid in dioxane/methylene chloride (1/9) was shaken at room temperature for 30 minutes.
  • the resin was collected by filtration and was washed with methylene chloride, 10% triethylamine-methylene chloride, methylene chloride, dimethylformamide, dimethylformamide-water (1:1), tetrahydrofuran, methanol, tetrahydrofuran, methanol and dimethylacetamide.
  • a mixture of the obtained resin, 293 mg of 2-chloro-5-bromopyrimidine and 211 ⁇ l of triethylamine was shaken at 55°C for 16 hours.
  • the resin was collected by filtration and washed with dimethylformamide, methylene chloride, 10% triethylamine-methylene chloride, methylene chloride, dimethylformamide, dimethylformamide-water (1:1), tetrahydrofuran, methanol, tetrahydrofuran, methanol and methylene chloride.
  • Whole amount of the obtained resin was treated with trifluoroacetic acid to obtain 61 mg of (S)-1-[trans-4-(5-bromopyrimidin-2-ylaminomethyl)cyclohexyl-amino]acetyl-2-cyanopyrrolidine hydrochloride (Example 5-37 in Table 5).
  • Example 6-1 The compounds of Examples 6-2 to 6-4 in Table 6 were obtained in the same manner as in Example 6-1 (3) and (4) by using the compound obtained in the above Example 6-1 (2) and corresponding starting materials.
  • L-thioprolineamide hydrochloride was synthesized according to the process described in the literature ( Ashworth et. al., Bioorg. Med. Chem. Lett., Vol. 6, pp. 2745-2748, 1996 ). 2.36 ml of chloroacetyl chloride was added to 150 ml of a dichloromethane solution containing 5.00 g of the thus obtained L-thioprolineamide hydrochloride and 8.67 ml of triethylamine under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added 4.8 ml of pyridine and 8.4 ml of trifluoroacetic anhydride, and the mixture was further stirred at room temperature for 1 hour.
  • t-4-tert-butoxycarbonylamino-4-methoxymethyl-r-1-cyclohexylamine or c-4-tert-butoxycarbonylamino-4-methoxymethyl-r-1-cyclohexylamine was obtained in the same manner as Reference Example 6-1, (1) to (5) or (6) except for using methoxymethyl chloride in place of methyl iodide in the step of Reference Example 6-1, (1).
  • this compound was treated with an acid to remove a protective group (tert-butoxycarbonyl group) to obtain 4-amino-4-methoxymethylpiperidine.
  • trans-4-(1,3-dioxo-5-methoxycarbonyl-2-isoindolinyl)cyclohexylamine hydrochloride (Reference Example 8-32 in Table 9) was obtained in the same manner as in Reference Example 8-25.
  • trans-4-[1,3-dioxo-5-(1-pyrrolidinyl)carbonyl-2-isoindolinyl]cyclohexylamine hydrochloride (Reference Example 8-33 in Table 9) was obtained in the same manner as in Reference Example 8-25.
  • trans-4-(benzyloxycarbonylamino)-1-cyclohexane-carboxamidine hydrochloride (a compound of Reference Example 8-35 (5)) (348 mg) as a starting material, by reacting the same with acetylacetone according to the method of Libman et al. (J. Chem. Soc., p. 2305, 1952 ), trans-1-benzyloxycarbonylamino-4-(4,6-dimethylpyrimidin-2-yl)cyclohexane (220 mg) was obtained.
  • a mixture comprising 500 mg of N-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine, 326 mg of 1,4-dichlorobutane, 805 mg of potassium carbonate, 70 mg of sodium iodide and ethanol-water (8 ml-2 ml) was stirred at 90°C for 12 days. Water was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and then, the solvent was removed under reduced pressure.
  • a mixture comprising 10 g of trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid, 7.93 g of 2-chloro-3-aminopyridine, 10.2 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 6.5 g of 4-dimethylaminopyridine, and 180 mL of N,N-dimethylformamide was stirred at room temperature for 15 hours. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution to make the solution alkaline, and extracted with ethyl acetate.
  • a mixture comprising 500 mg of trans-4-tert-butoxycarbonylamino-N-(2-chloro-3-pyridyl)cyclohexanecarboxamide (Reference Example 8-40), 858 mg of 2,4-bis(4-methoxyphenyl)-1,3-dithio-2,4-diphosphetane-2,4-disulfide and 10 mL of tetrahydrofuran was stirred at 60°C for 18 hours. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (solvent: chloroform-methanol 50:1).
  • trans-4-(benzyloxycarbonylamino)cyclohexanecarboxylic acid and 2-aminophenol in the same manner as in Reference Example 8-40, trans-4-benzyloxycarbonylamino-N-(2-hydroxyphenyl)cyclohexanecarboxamide was obtained.
  • This compound was stirred in 2 ml of 4N hydrochloric acid-dioxane, and 2 ml of ethanol for 8 hours, and then, the reaction mixture was concentrated. An aqueous 10% sodium hydroxide solution was added thereto. The mixture was extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 55 mg of t-4-dimethylamino-1-methyl-r-1-cyclohexylamine (Reference Example 8-57 in Table 9).

Claims (19)

  1. Composé de cycle à 5 membres aliphatique contenant un atome d'azote représenté par la formule [I] :
    Figure imgb0350
     dans lequel les symboles dans la formule ont les significations suivantes ;
    A : -CH2- ou -S-,
    B : CH,
    R1 : H, un groupe alkyle en C1-6, un groupe hydroxy alkyle en C1-6 ou un groupe (alcoxy en C1-6,) alkyle en C1-6,
    X : une simple liaison, -Alk-CO-, -COCH2-, -Alk-O-, -O-CH2-, -SO2-, -S-, -COO-, -CON(R3)CH2-, -Alk-CON(R3)CH2-, ou - NHCH2-, où la liaison à une extrémité droite dans chaque définition du X ci-dessus représente une liaison avec B,
    R3 : un atome d'hydrogène ou un groupe alkyle en C1-6,
    Alk : un groupe alkylène en C1-6, et
    R2 : un groupe cyclique choisi parmi :
    un groupe phényle, un groupe cyclohexyle, un groupe cyclopropyle, un groupe pyrrolidinyle, un groupe imidazolidinyle, un groupe pyrazolidinyle, un groupe pyrrolyle, un groupe imidazolyle, un groupe pyrazolyle, un groupe furyle, un groupe oxazolyle, un groupe isoxazolyle, un groupe thiényle, un groupe thiazolyle, un groupe isothiazolyle, un groupe pipéridyle, un groupe pipérazinyle, un groupe morpholinyle, un groupe thiomorpholinyle, un groupe pyridyle, un groupe pyrimidinyle, un groupe pyrazinyle, un groupe pyridazinyle, un groupe isoindolinyle, un groupe indolinyle, un groupe thiazolopyridyle, un groupe pyrrolopyridyle, un groupe dihydropyrrolopyridyle, un groupe benzoxazolyle, un groupe quinolyle, un groupe isoquinolyle, un groupe quinazolinyle, un groupe isoindolyle, un groupe indolyle, et les groupes cycliques partiellement ou complètement saturés de ceux-ci,
    qui peuvent avoir 1 à 3 substituant(s) qui sont identiques ou différents et choisis parmi :
    un atome d'halogène, un groupe cyano, un groupe nitro, un groupe amino, un groupe oxo, un groupe alkyle en C1-6, un groupe alcoxy en C1-6, un groupe alcanoyle en C2-7, un groupe alcoxycarbonyle en C1-6, un groupe alcoxycarbonylamino en C 1-6, un groupe cycloalkylcarbonyle en C3-8, un groupe halogéno-alkyle en C1-6, un groupe halogéno-alkylcarbonyle en C1-6, un groupe carbonyle substitué par un groupe hétérocyclique aliphatique de 5 à 6 membres monocyclique contenant un atome d'azote, un groupe hétérocyclique aromatique de 6 membres monocyclique contenant un atome d'azote, un groupe phényle, un groupe alkylthio en C1-6 et un groupe aminosulfonyle,
    ou un sel pharmaceutiquement acceptable de celui-ci.
  2. Composé selon la revendication 1, dans lequel R2 est un groupe cyclique choisi parmi :
    un groupe pipéridyle, un groupe pipérazinyle, un groupe morpholinyle, un groupe indolinyle, un groupe isoindolinyle et un groupe thiazolopyridyle,
    qui peut avoir des substituants.
  3. Composé selon la revendication 1, dans lequel R2 est un groupe cyclique choisi parmi :
    un groupe pipéridyle, un groupe pipérazinyle, un groupe morpholinyle, un groupe indolinyle, un groupe isoindolinyle et un groupe thiazolopyridyle,
    qui peut avoir 1 à 3 substituant(s), choisis parmi :
    un groupe oxo, un groupe alcanoyle en C2-7, un groupe cycloalkylcarbonyle en C3-8, un groupe alcoxycarbonyle en C 1-6 et un groupe carbonyle substitué par un groupe hétérocyclique aliphatique de 5 à 6 membres monocyclique contenant un atome d'azote.
  4. Composé selon l'une quelconque des revendications 1 à 3, dans lequel X est une simple liaison et R2 est un groupe hétérocyclique contenant un atome d'azote monocyclique ou bicyclique qui peut être substitué.
  5. Composé selon la revendication 1, dans lequel X est une simple liaison, A est -CH2- et R1 est un atome d'hydrogène ou un groupe alkyle en C1-6.
  6. Composé selon la revendication 2, dans lequel X est une simple liaison, A est -CH2- et R1 est un atome d'hydrogène ou un groupe alkyle en C1-6.
  7. Composé selon la revendication 3, dans lequel X est une simple liaison, A est -CH2- et R1 est un atome d'hydrogène ou un groupe alkyle en C1-6.
  8. Composé selon la revendication 4, dans lequel X est une simple liaison, A est -CH2- et R1 est un atome d'hydrogène ou un groupe alkyle en C1-6.
  9. Composé selon la revendication 1, dans lequel X est une simple liaison, A est -S- et R1 est un atome d'hydrogène ou un groupe alkyle en C1-6.
  10. Composé selon l'une quelconque des revendications 1 à 9, dans lequel le composé possède la structure partielle suivante :
    Figure imgb0351
     ou un sel pharmaceutiquement acceptable de celui-ci.
  11. Composé selon la revendication 1 choisi dans le groupe suivant constitué de :
    la (S)-2-cyano-1-[t-4-(4-acétyl-1-pipérazinyl)-1-méthyl-r-1-cyclohexylamino]acétylpyrrolidine ;
    la (S)-2-cyano-1-[trans-4-(1,3-dioxo-2-isoindolinyl)-cyclohexylamino]acétylpyrrolidine ;
    la (S)-2-cyano-1-(trans-4-morpholinocyclohexylamino)-acétylpyrrolidine ;
    la (S)-2-cyano-1-[trans-4-(thiazolo[5,4-b]pyridin-2-yl)-cyclohexylamino]acétylpyrrolidine ; et
    la (S)-2-cyano-1-[t-4-(4-propionyl-1-pipérazinyl)-1-méthyl-r-1-cyclohexylaminolacétylpyrrolidine ;
    ou un sel pharmaceutiquement acceptable de celles-ci.
  12. Procédé pour préparer un composé de cycle à 5 membres aliphatique contenant un atome d'azote représenté par la formule [I] :
    Figure imgb0352
     dans lequel les symboles dans la formule ont les significations telles que définies selon la revendication 1, ou un sel pharmaceutiquement acceptable de celui-ci, qui comprend la réaction d'un composé représenté par la formule [II] :
    Figure imgb0353
     dans laquelle A représente -CH2- ou -S- et Z1 représente un résidu réactif, avec un composé représenté par la formule [III] :
    Figure imgb0354
     dans laquelle R1, R2, B et X ont les mêmes significations que définies ci-dessus, ou des sels de ceux-ci, et éventuellement la transformation du produit en un sel pharmaceutiquement acceptable de celui-ci.
  13. Utilisation d'un composé selon l'une quelconque des revendications 1 à 11 dans un médicament.
  14. Utilisation d'un composé selon l'une quelconque des revendications 1 à 11 dans la préparation d'un médicament destiné à inhiber la dipeptidylpeptidase IV.
  15. Utilisation d'un composé selon la revendication 14 dans la préparation d'un médicament destiné au traitement ou à la prophylaxie d'une maladie qui devrait être améliorée par l'inhibition de l'activité dipeptidylpeptidase IV.
  16. Utilisation d'un composé selon la revendication 14 dans la préparation d'un médicament destiné au traitement ou à la prophylaxie du diabète.
  17. Utilisation d'un composé selon la revendication 14 dans la préparation d'un médicament destiné au traitement ou à la prophylaxie du diabète de type 2.
  18. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 11 comme ingrédient actif.
  19. Composition pharmaceutique selon la revendication 18, dans laquelle la composition pharmaceutique est un inhibiteur de la dipeptidylpeptidase IV.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7803753B2 (en) 2005-01-10 2010-09-28 Arena Pharmaceuticals, Inc. Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
US7816364B2 (en) 2006-04-11 2010-10-19 Arena Pharmaceuticals, Inc. GRP119 receptor agonists in methods of increasing bone mass and of treating osteoporosis and other conditions characterized by low bone mass, and combination therapy relating thereto
US7833730B2 (en) 2006-04-11 2010-11-16 Arena Pharmaceuticals, Inc. Methods of using GPR119 to identify compounds useful for increasing bone mass in an individual
US7838254B2 (en) 2008-04-07 2010-11-23 Arena Pharmaceuticals, Inc. Methods of using GPR119 to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY

Families Citing this family (115)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10123163A1 (de) * 2001-05-09 2003-01-16 Gruenenthal Gmbh Substituierte Cyclohexan-1,4-diaminderivate
DE60221983T2 (de) 2001-06-27 2008-05-15 Smithkline Beecham Corp. Fluorpyrrolidine als dipeptidyl-peptidase inhibitoren
DE60235212D1 (de) 2001-06-27 2010-03-11 Smithkline Beecham Corp Fluoropyrrolidine als Dipeptidylpeptidasehemmer
DE60223920T2 (de) 2001-06-27 2008-11-13 Smithkline Beecham Corp. Pyrrolidine als dipeptidyl-peptidase-inhibitoren
US6861440B2 (en) 2001-10-26 2005-03-01 Hoffmann-La Roche Inc. DPP IV inhibitors
EP1338595B1 (fr) 2002-02-25 2006-05-03 Eisai Co., Ltd. Dérivés de Xanthines servant d'inhibiteurs de DPP-IV
SI1480961T1 (sl) * 2002-02-28 2007-06-30 Prosidion Ltd Inhibitorji dpiv na osnovi glutaminila
HUP0200849A2 (hu) * 2002-03-06 2004-08-30 Sanofi-Synthelabo N-aminoacetil-2-ciano-pirrolidin-származékok, e vegyületeket tartalmazó gyógyszerkészítmények és eljárás előállításukra
DE10213051B4 (de) * 2002-03-23 2013-03-07 Grünenthal GmbH Substituierte 4-Aminocyclohexanole
HUP0202001A2 (hu) 2002-06-14 2005-08-29 Sanofi-Aventis DDP-IV gátló hatású azabiciklooktán- és nonánszármazékok
WO2004007446A1 (fr) * 2002-07-10 2004-01-22 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive de l'azetidine ou ses sels
TW200401635A (en) 2002-07-23 2004-02-01 Yamanouchi Pharma Co Ltd 2-Cyano-4-fluoropyrrolidine derivative or salt thereof
US7238724B2 (en) 2002-09-19 2007-07-03 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US7262207B2 (en) 2002-09-19 2007-08-28 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
GB0224830D0 (en) 2002-10-24 2002-12-04 Sterix Ltd Compound
CA2501228A1 (fr) * 2002-10-24 2004-05-06 Sterix Limited Inhibiteurs de 11-beta-hydroxy steroide dehydrogenase de type 1 et de type 2
DE10252666A1 (de) * 2002-11-11 2004-08-05 Grünenthal GmbH N-Piperidyl-cyclohexan-Derivate
US7550590B2 (en) * 2003-03-25 2009-06-23 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
ZA200507112B (en) * 2003-03-31 2007-03-28 Taisho Pharmaceutical Co Ltd Novel quinoline, tetrahydroquinazoline, and pyrimidine derivatives and methods of treatment related to the use thereof
EP1464335A3 (fr) * 2003-03-31 2007-05-09 Taisho Pharmaceutical Co. Ltd. Derivés de quinolines, tetrahydroquinolines et pyrimidines comme antagonistes du MCH
US20090137658A1 (en) * 2003-05-06 2009-05-28 Tanabe Seiyaku Co.,Ltd. Benzenesulfonic acid salt compounds
GB0310593D0 (en) * 2003-05-08 2003-06-11 Leuven K U Res & Dev Peptidic prodrugs
CA2529443C (fr) 2003-06-20 2012-06-05 F. Hoffmann-La Roche Ag Derives de pyrido[2,1-a]isoquinoline utilises comme inhibiteurs de dpp-iv
BRPI0411509A (pt) 2003-06-20 2006-07-25 Hoffmann La Roche compostos, processo para a sua manufatura, composições farmacêuticas que compreendem os mesmos, método para tratamento e/ou profilaxia de enfermidades que estão associadas com dpp-iv e sua utilização
US7169926B1 (en) 2003-08-13 2007-01-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
BRPI0413452A (pt) * 2003-08-13 2006-10-17 Takeda Pharmaceutical composto, composição farmacêutica, kit, artigo de fabricação, e, métodos de inibir dpp-iv, terapêutico e de tratar um estado de doença, cáncer, distúrbios autoimunes, uma condição einfecção por hiv
US7678909B1 (en) 2003-08-13 2010-03-16 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
HU227684B1 (en) * 2003-08-29 2011-11-28 Sanofi Aventis Adamantane and azabicyclo-octane and nonane derivatives and their use as dpp-iv inhibitors
US7205409B2 (en) 2003-09-04 2007-04-17 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US20050065144A1 (en) * 2003-09-08 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors
JP2007505121A (ja) * 2003-09-08 2007-03-08 武田薬品工業株式会社 ジペプチジルぺプチダーゼ阻害剤
US7291744B2 (en) 2003-11-13 2007-11-06 Bristol-Myers Squibb Company N-ureidoalkyl-amino compounds as modulators of chemokine receptor activity
EP2839832A3 (fr) 2003-11-17 2015-06-24 Novartis AG Utilisation d'inhibiteurs de la dipeptidyl peptidase IV
WO2005056541A1 (fr) 2003-12-11 2005-06-23 Mitsubishi Pharma Corporation Derives d'acides $g(a)-amino et leur utilisation comme medicaments
CA2549860A1 (fr) * 2003-12-19 2005-06-30 Altana Pharma Ag Intermediaires pour la preparation de derives de dihydropyrano-imidazopyridines tricycliques
SI1715893T1 (sl) 2004-01-20 2009-12-31 Novartis Pharma Ag Direktna kompresijska formulacija in postopek
SI1712547T1 (sl) * 2004-02-05 2012-04-30 Kyorin Seiyaku Kk Bicikloestrski derivat
JP3997255B2 (ja) 2004-02-13 2007-10-24 ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー アンドロゲンレセプターモジュレーター
CA2554378A1 (fr) * 2004-02-18 2005-08-25 Kyorin Pharmaceutical Co., Ltd. Derive de bicycloamide
US7514571B2 (en) * 2004-02-27 2009-04-07 Kyorin Pharmaceutical Co., Ltd. Bicyclo derivative
US7348346B2 (en) 2004-03-08 2008-03-25 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
US7732446B1 (en) 2004-03-11 2010-06-08 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
AU2004318013B8 (en) * 2004-03-15 2011-10-06 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
EP1730122A2 (fr) * 2004-03-30 2006-12-13 Taisho Pharmaceutical Co., Ltd Derives de pyrimidine et procedes de traitement lies a l'utilisation de ceux-ci
BRPI0509759A (pt) 2004-04-13 2007-10-16 Warner Lambert Co moduladores de androgênio
CA2562672C (fr) 2004-04-22 2009-09-29 Warner-Lambert Company Llc Derives du type 4-cyano-phenoxy utilises comme modulateurs d'androgenes
TW200604167A (en) * 2004-04-27 2006-02-01 Astellas Pharma Inc Pyrrolidine derivatives
DE102004023632A1 (de) * 2004-05-10 2005-12-08 Grünenthal GmbH Substituierte Cyclohexylcarbonsäure-Derivate
DE102004023635A1 (de) 2004-05-10 2006-04-13 Grünenthal GmbH Heteroarylsubstituierte Cyclohexyl-1,4-diamin-Derivate
DE102004023507A1 (de) 2004-05-10 2005-12-01 Grünenthal GmbH Substituierte Cyclohexylessigsäure-Derivate
US7687638B2 (en) * 2004-06-04 2010-03-30 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
WO2006006065A1 (fr) * 2004-07-08 2006-01-19 Warner-Lambert Company Llc Modulateurs d'androgenes
WO2006019965A2 (fr) 2004-07-16 2006-02-23 Takeda San Diego, Inc. Inhibiteurs de la dipeptidyl peptidase
JP2008507541A (ja) 2004-07-23 2008-03-13 ロイヤルティ，スーザン・マリー ペプチダーゼ阻害剤
WO2006011035A1 (fr) * 2004-07-23 2006-02-02 Glenmark Pharmaceuticals Ltd. Nouveaux inhibiteurs de la dipeptidyl peptidase iv, procede de preparation de ces inhibiteurs et compositions contenant ces inhibiteurs
WO2006012441A1 (fr) * 2004-07-23 2006-02-02 Susan Marie Royalty Inhibiteurs de peptidase
US20080090863A1 (en) * 2004-09-30 2008-04-17 Taisho Pharmaceutical Co., Ltd. Pyridine Derivatives and Their Use as Medicaments for Treating Diseases Related to Mch Receptor
EP1799639B1 (fr) 2004-10-12 2013-09-04 Glenmark Pharmaceuticals S.A. Nouveaux inhibiteurs de dipeptidyle peptidase iv, compositions pharmaceutiques en contenant, et leur procédé de préparation
UA90690C2 (ru) * 2004-10-12 2010-05-25 Гленмарк Фармасьютикалс С.А. Ингибиторы дипептидилпептидазы iv, процесс их получения и фармацевтическая композиция, которая их содержит (варианты)
EP2805953B1 (fr) * 2004-12-21 2016-03-09 Takeda Pharmaceutical Company Limited Inhibiteurs de peptidase dipeptidyl
EP1879881A2 (fr) * 2005-04-14 2008-01-23 Bristol-Myers Squibb Company Inhibiteurs de la 11-beta hydroxysteroide deshydrogenase de type i
ZA200708179B (en) * 2005-04-22 2009-12-30 Alantos Pharmaceuticals Holding Inc Dipeptidyl peptidase-IV inhibitors
TW200724139A (en) 2005-05-05 2007-07-01 Warner Lambert Co Androgen modulators
US7521557B2 (en) * 2005-05-20 2009-04-21 Bristol-Myers Squibb Company Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods
EP1891550A2 (fr) * 2005-05-31 2008-02-27 Koninklijke Philips Electronics N.V. Support de stockage portatif, dispositif hote et procede permettant d'acceder au contenu du support de stockage portatif par le dispositif hote
WO2006133160A2 (fr) 2005-06-06 2006-12-14 Georgetown University Compositions et procedes de lipomodelage
MY152185A (en) 2005-06-10 2014-08-29 Novartis Ag Modified release 1-[(3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(s)-carbonitrile formulation
EP1760076A1 (fr) 2005-09-02 2007-03-07 Ferring B.V. Inhibiteur de FAP
WO2007033350A1 (fr) 2005-09-14 2007-03-22 Takeda Pharmaceutical Company Limited Inhibiteurs de la dipeptidyl peptidase permettant de traiter le diabete
CA2622608C (fr) * 2005-09-14 2014-08-19 Takeda Pharmaceutical Company Limited Administration d'inhibiteurs de dipeptidyl peptidase
EP1924567B1 (fr) 2005-09-16 2012-08-22 Takeda Pharmaceutical Company Limited Inhibiteurs de dipeptidylpeptidase
TW200745079A (en) * 2005-09-16 2007-12-16 Takeda Pharmaceuticals Co Polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor
TW200745080A (en) * 2005-09-16 2007-12-16 Takeda Pharmaceuticals Co Polymorphs of tartrate salt of 2-[2-(3-(R)-amino-piperidin-1-yl)-5-fluoro-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile and methods of use therefor
GB0526291D0 (en) 2005-12-23 2006-02-01 Prosidion Ltd Therapeutic method
AU2007224066B2 (en) * 2006-03-08 2011-10-27 Kyorin Pharmaceutical Co., Ltd. Method for producing aminoacetylpyrrolidinecarbonitrile derivative and production intermediate thereof
WO2007112347A1 (fr) 2006-03-28 2007-10-04 Takeda Pharmaceutical Company Limited Inhibiteurs de la dipeptidyl peptidase
JP2009531456A (ja) * 2006-03-28 2009-09-03 武田薬品工業株式会社 （ｒ）−３−アミノピペリジン二塩酸塩の調製
WO2007148185A2 (fr) * 2006-06-21 2007-12-27 Pfizer Products Inc. 3-amino-pyrrolidino-4-lactames substitués
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
TW200838536A (en) * 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
JP2010120851A (ja) * 2007-02-09 2010-06-03 Kyorin Pharmaceut Co Ltd 二量化シクロ誘導体
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
US8143427B2 (en) * 2007-03-22 2012-03-27 Kyorin Pharmaceutical Co., Ltd. Method for producing aminoacetylpyrrolidinecarbonitrile derivative
JP5616630B2 (ja) 2007-04-03 2014-10-29 田辺三菱製薬株式会社 ジペプチジルペプチダーゼ４阻害化合物と甘味料との併用
GB2465132B (en) * 2007-09-21 2012-06-06 Lupin Ltd Compounds as dipeptidyl peptidase IV (DPP IV) inhibitors
WO2009116067A2 (fr) * 2008-01-10 2009-09-24 Sun Pharma Advanced Research Company Limited Nouveaux dérivés d'acyle cyanopyrrolidines
CL2008003653A1 (es) * 2008-01-17 2010-03-05 Mitsubishi Tanabe Pharma Corp Uso de un inhibidor de sglt derivado de glucopiranosilo y un inhibidor de dppiv seleccionado para tratar la diabetes; y composicion farmaceutica.
US8278313B2 (en) 2008-03-11 2012-10-02 Abbott Laboratories Macrocyclic spiro pyrimidine derivatives
US8436005B2 (en) 2008-04-03 2013-05-07 Abbott Laboratories Macrocyclic pyrimidine derivatives
JP5476305B2 (ja) * 2008-08-07 2014-04-23 杏林製薬株式会社 ビシクロ［２．２．２］オクチルアミン誘導体の製造方法
WO2010018866A1 (fr) * 2008-08-14 2010-02-18 杏林製薬株式会社 Composition pharmaceutique stabilisée
WO2010039124A1 (fr) * 2008-09-30 2010-04-08 Mitsubishi Tanabe Pharma Corporation Composés de sel d’acide benzène sulfonique
US7965235B2 (en) * 2009-02-24 2011-06-21 Raytheon Company Multi-channel thinned TR module architecture
US7876263B2 (en) * 2009-02-24 2011-01-25 Raytheon Company Asymmetrically thinned active array TR module and antenna architecture
GB2483614B (en) 2009-06-18 2014-12-03 Lupin Ltd 2-Amino-2- [8-(dimethyl carbamoyl)- 8-aza- bicyclo [3.2.1] oct-3-yl]-exo- ethanoyl derivatives as potent dpp-iv inhibitors
AR077642A1 (es) 2009-07-09 2011-09-14 Arena Pharm Inc Moduladores del metabolismo y el tratamiento de trastornos relacionados con el mismo
BR112012025592A2 (pt) 2010-04-06 2019-09-24 Arena Pharm Inc moduladores do receptor de gpr119 e o tratamento de distúrbios relacionados com os mesmos
AU2011305525B2 (en) 2010-09-22 2016-08-18 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
WO2012135570A1 (fr) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles qui lui sont associés
US20140066369A1 (en) 2011-04-19 2014-03-06 Arena Pharmaceuticals, Inc. Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
US20140051714A1 (en) 2011-04-22 2014-02-20 Arena Pharmaceuticals, Inc. Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
WO2012145603A1 (fr) 2011-04-22 2012-10-26 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles liés à celui-ci
WO2012170702A1 (fr) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés à celui-ci
EP2729468A4 (fr) * 2011-07-05 2015-03-18 Merck Sharp & Dohme Hétérocycles tricycliques utiles comme inhibiteurs de la dipeptidyl peptidase-iv
WO2013055910A1 (fr) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
CN102875558A (zh) * 2012-11-05 2013-01-16 贵州大学 2-氯-4-取代-8-硝基苯并呋喃[3,2-d]嘧啶类化合物及其制备方法和用途
WO2014074668A1 (fr) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulateurs de gpr119 et traitement de troubles associés à ceux-ci
MY176401A (en) 2014-04-24 2020-08-05 Mitsubishi Tanabe Pharma Corp Novel disubstituted 1,2,4-triazine compound
KR20180006881A (ko) 2015-03-09 2018-01-19 인테크린 테라퓨틱스, 아이엔씨. 비알코올성 지방간 질환 및/또는 지방이영양증의 치료 방법
JP2020515639A (ja) 2017-04-03 2020-05-28 コヒラス・バイオサイエンシズ・インコーポレイテッド 進行性核上性麻痺の処置のためのＰＰＡＲγアゴニスト
WO2019154859A1 (fr) * 2018-02-06 2019-08-15 Universität Heidelberg Inhibiteur de fap
CN108218865B (zh) * 2018-03-31 2020-06-26 济南市儿童医院 一种酰胺类衍生物及其在心脑血管方面的应用
CN108456207B (zh) * 2018-03-31 2020-11-20 浙江药苑生物科技有限公司 一种酰胺类衍生物及其在心脑血管方面的应用
CN114288292B (zh) * 2021-12-10 2023-06-13 中南大学湘雅医院 芳香族化合物作为神经丛素蛋白-b2的激活剂以及在制备治疗骨质疏松症药物中的应用
WO2023233024A1 (fr) 2022-06-03 2023-12-07 Universiteit Antwerpen Composés liant dpp9

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096295A2 (fr) * 2000-06-13 2001-12-20 Novartis Ag Composes organiques

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6512481B1 (en) * 1996-10-10 2003-01-28 Teratech Corporation Communication system using geographic position data
TW492957B (en) 1996-11-07 2002-07-01 Novartis Ag N-substituted 2-cyanopyrrolidnes
US6011155A (en) 1996-11-07 2000-01-04 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6316612B1 (en) * 1997-08-22 2001-11-13 Ribozyme Pharmaceuticals, Inc. Xylofuranosly-containing nucleoside phosphoramidites and polynucleotides
US6484015B1 (en) * 1997-10-27 2002-11-19 Lucent Technologies Inc. Portable telephone antenna
CO5150173A1 (es) * 1998-12-10 2002-04-29 Novartis Ag Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv
US6107317A (en) * 1999-06-24 2000-08-22 Novartis Ag N-(substituted glycyl)-thiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6110949A (en) * 1999-06-24 2000-08-29 Novartis Ag N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
JP3551122B2 (ja) * 2000-04-07 2004-08-04 日本電気株式会社 携帯電話装置
US6432969B1 (en) 2000-06-13 2002-08-13 Novartis Ag N-(substituted glycyl)-2 cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
WO2002051836A1 (fr) 2000-12-27 2002-07-04 Kyowa Hakko Kogyo Co., Ltd. Inhibiteur de dipeptidyl peptidase iv

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096295A2 (fr) * 2000-06-13 2001-12-20 Novartis Ag Composes organiques

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8022034B2 (en) 2005-01-10 2011-09-20 Arena Pharmaceuticals, Inc. Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
US7803754B2 (en) 2005-01-10 2010-09-28 Arena Pharmaceuticals, Inc. Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
US8198232B2 (en) 2005-01-10 2012-06-12 Arena Pharmaceuticals, Inc. Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
US8030270B2 (en) 2005-01-10 2011-10-04 Arena Pharmaceuticals, Inc. Methods for identifying GLP-1 secretagogues
US7803753B2 (en) 2005-01-10 2010-09-28 Arena Pharmaceuticals, Inc. Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
US8003597B2 (en) 2005-01-10 2011-08-23 Arena Pharmaceuticals, Inc. Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
US8026074B2 (en) 2006-04-11 2011-09-27 Arena Pharmaceuticals, Inc. Methods of using GPR119 to identify compounds useful for increasing bone mass in an individual
US8017574B2 (en) 2006-04-11 2011-09-13 Arena Pharmaceuticals, Inc. Methods of preparing pharmaceutical compositions comprising GPR119 agonists having the effect of glucose-dependent insulinotropic peptide secretagogues
US8026212B2 (en) 2006-04-11 2011-09-27 Arena Pharmaceuticals, Inc. Methods of preparing pharmaceutical compositions comprising GPR119 agonists having the effect of glucose-dependent insulinotropic peptide secretatgogues
US7833730B2 (en) 2006-04-11 2010-11-16 Arena Pharmaceuticals, Inc. Methods of using GPR119 to identify compounds useful for increasing bone mass in an individual
US8101626B2 (en) 2006-04-11 2012-01-24 Arena Pharmaceuticals, Inc. GPR119 receptor agonists in methods of increasing bone mass and of treating osteoporosis and other conditions characterized by low bone mass, and combination therapy relating thereto
US7816364B2 (en) 2006-04-11 2010-10-19 Arena Pharmaceuticals, Inc. GRP119 receptor agonists in methods of increasing bone mass and of treating osteoporosis and other conditions characterized by low bone mass, and combination therapy relating thereto
US8580526B2 (en) 2006-04-11 2013-11-12 Arena Pharmaceuticals, Inc. Methods of using GPR119 receptor to identify compounds which stimulate glucose-dependent insulinotropic peptide secretion
US7838254B2 (en) 2008-04-07 2010-11-23 Arena Pharmaceuticals, Inc. Methods of using GPR119 to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY
US8486646B2 (en) 2008-04-07 2013-07-16 Arena Pharmaceuticals, Inc. Methods of using a G protein-coupled receptor to identify peptide YY (PYY) secretagogues
US8883714B2 (en) 2008-04-07 2014-11-11 Arena Pharmaceuticals, Inc. Pharmaceutical compositions comprising GPR119 agonists which act as peptide YY (PYY) secretagogues

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AU2001294196B2 (en) 2005-11-17
KR100526091B1 (ko) 2005-11-08
HK1055301A1 (en) 2004-01-02
EP1323710A4 (fr) 2005-05-18
TWI290919B (en) 2007-12-11
IL154893A (en) 2008-04-13
ATE407924T1 (de) 2008-09-15
DE60135862D1 (de) 2008-10-30
US7666869B2 (en) 2010-02-23
AU9419701A (en) 2002-04-22
PT1323710E (pt) 2008-11-25
BR0114436A (pt) 2003-07-01
NO20031490D0 (no) 2003-04-02
KR20030041149A (ko) 2003-05-23
PT1325910E (pt) 2008-10-27
NO324519B1 (no) 2007-11-12
US20040229926A1 (en) 2004-11-18
CA2424964C (fr) 2007-12-04
NZ524974A (en) 2005-10-28
WO2002030890A8 (fr) 2002-05-16
US7160877B2 (en) 2007-01-09
CN1280269C (zh) 2006-10-18
AU2001294197B2 (en) 2004-09-16
CA2424964A1 (fr) 2002-04-18
EP1323710A1 (fr) 2003-07-02
EP1325910A4 (fr) 2005-05-18
EP1325910B1 (fr) 2008-09-17
US6849622B2 (en) 2005-02-01
IL154893A0 (en) 2003-10-31
DK1325910T3 (da) 2008-11-10
ES2312472T3 (es) 2009-03-01
PL362545A1 (en) 2004-11-02
WO2002030890A1 (fr) 2002-04-18
CN1468217A (zh) 2004-01-14
CA2424600A1 (fr) 2003-04-02
CN1468216A (zh) 2004-01-14
HK1055302A1 (en) 2004-01-02
DK1323710T3 (da) 2008-12-01
MXPA03003007A (es) 2003-07-14
US20080153821A1 (en) 2008-06-26
US20040063935A1 (en) 2004-04-01
NZ525630A (en) 2004-10-29
HUP0303391A2 (hu) 2004-03-01
CN1257891C (zh) 2006-05-31
HUP0303391A3 (en) 2004-04-28
ATE408597T1 (de) 2008-10-15
US20060241146A1 (en) 2006-10-26
DE60135764D1 (de) 2008-10-23
US7332487B2 (en) 2008-02-19
ES2312471T3 (es) 2009-03-01
US7138397B2 (en) 2006-11-21
AU9419601A (en) 2002-04-22
KR100555014B1 (ko) 2006-03-03
CA2424600C (fr) 2008-12-02
KR20030041148A (ko) 2003-05-23
WO2002030891A8 (fr) 2002-05-16
WO2002030891A1 (fr) 2002-04-18
NO20031490L (no) 2003-06-02
MXPA03003006A (es) 2003-07-14
US20050054678A1 (en) 2005-03-10
AU2001294197C1 (en) 2005-05-19
EP1325910A1 (fr) 2003-07-09

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